1. Staging in Cancer: Order out of Chaos Lily L. Lai, MD, FACS Chair, Clinical Cancer Committee City of Hope

2. Life

3. The one thing that (scientists) do not and must not tolerate is disorder. The whole aim of theoretical science is to carry to the highest possible and conscious degree the perceptual reduction of chaos that began in so lowly and (in all probability) unconscious a way with the origin of life. George Gaylord Simpson (Principles of Animal Taxonomy, 1961)

4. Cancer

5. Outline History Rationale Application Types of Staging Future

6. Cuthbert Dukes Pierre Denoix History Frederic Greene Mahul Amin

7. Dukes 1932 AB C +LN s

8. Astler & Collier 1954 + LNs AB2B1C1C2

9. Tis T1 T2 T3 T4 TNM 1968

10. Staging: why? Cancer care expectations –To aid the clinician in planning treatment –To give some indication of prognosis –To assist in evaluating the results of treatment –To facilitate the exchange of information between treatment centers –To contribute to continuing investigations of human malignancies UICC, 1958 AJCC Cancer Staging Manual (v. 7), 2010

11. Staging: Why? Institutional requirements –American College of Surgeons, Commission on Cancer, Clinical Cancer Program Standards for evaluation of cancer clinics since 1931 Accreditation of institution as providing quality cancer care Surveys of programs conducted every 3 years –Standards of the ACoS, CoC specific to Staging 90% of cases are correctly staged Clinical staging occurs preoperatively, pre-treatment Completed staging (Collaborative Stage) within 4 months of initiating treatment

12. The three axes of cancer classification Topographic site Location can change patterns of progression Rectal v. colon Head and neck v. lung Histology Kind of cell responds to different treatments Nonsmall cell lung ca v. small cell lung cancer Melanoma v. basal cell cancer of the skin Anatomic extent (Staging) Degree of local and systemic involvement Topographic site (disease site) Histologic type Anatomic extent (TNM) Patient’s Disease

13. Anatomic Staging Based on three components T The extent of the primary tumor N The absence or presence and extent of regional lymph node metastasis M The absence or presence of distant metastasis

14. Primary Tumor (T) Regional Lymph nodes (N) Distant Metastases (M) Cannot be assessed TxNxMx No evidenceT0N0M0 In situTis Increasing involvement T1 - 4N 1 - 3M1

15. Tumor (T) cT can be based on palpation or imaging pT requires adequate resection of tumor If tumor is removed in pieces, an effort at reconstruction is needed to approximate the native size prior to manipulation (add the pieces together) In cases with > 1 tumor in the same site, the tumor that is the highest T category is used and a parenthesis after T is used to designate multiplicity: T1 (m) or T1 (3) In cases with simultaneous bilateral tumors, each tumor is staged –as independent tumors (breast) –as metastasis (lung) Unknown primary is based on clinical suspicion of primary origin and is designated T0 (not Tx)

16. Tumor (T): Breast Cancer >5 cm tumor T1T2T3T4

17. Tumor (T): Colorectal Cancer

18. Tumor (T): Lung Cancer T1T2 T3 T4

19. Accurate T-staging predicts outcome Staging outcomes AJCC v. 6 Staging outcomes AJCC v. 7

20. Regional Lymph Nodes (N) pN entails removal of a sufficient number of LNs to ensure appropriate staging –Colon (>12) –Gastric (>16) If number of LNs reveals negative nodes but the total < suggested LN dissection, then N = pN0 –May affect treatment Sentinel lymph node assessment is appropriate in some sites (breast, melanoma) Isolated tumor cell clusters (ITC) (< 0.2mm, less than 200 cells) are staged as N0(i+) Micrometastases (> 0.2 mm, <2 mm, more than 200 cells) are staged as N1mi –Breast T0-1,N1mi = St. 1B

21. Nodes (N)

22. Absolute number of positive LNs predict survival Greene, CA Cancer J Clin 2008; 58:180- 90 T1, 2, N1 T3, 4, N1 any T, N2

23. Total number of LNs removed predicts survival Greene, CA Cancer J Clin 2008; 58:180- 90

24. Location of lymph nodes removed predicts survival NXRegional node cannot be addressed N0No regional lymph node metastases N1Metastasis in ipsilateral peribronchial +/- ipsilateral hilar and intrapulmonary nodes, including direct extension N2Metastasis in ipsilateral mediastinal +/- subcarinal nodes N3Metastases in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular nodes

25. Metastasis (M) Metastasis can be staged clinically (cM) or pathologically (pM) cM is adequate if T and N have meet pathologic staging –Biopsy of metastasis not absolutely needed If metastasis has tissue diagnosis, then pM If metastasis identified, any T and any N is acceptable including TX, NX, M1

26. Metastases

27. Stage Grouping STAGE 0 T is N-N- M-M- I+-- II++/-- III+/-+- IV+/- +

28. Descriptors Indication SuffixmPresence of multiple primary T pT(m)NM PrefixyPost initial treatment (staging after preop treatment) ycTNM or ypTNM rRecurrent tumor after a disease free interval rTNM aAutopsyaTNM

29. Other factors Histopathologic subtype –Adenocarcinoma, SCCA Histology/Grade –Poor, mod, well differentiated –Undifferentiated Lymphovascular invasion Residual tumor –RX, R0 – 2 resections Site-specific factors –Breast: ER, PR, Her2-neu –Thyroid: Age –CRC: Microsatellite instability, MMR, K-ras status –Prostate: PSA, Gleason’s Score

30. Site specific factors: Prostate Cancer STAGETNMPSAGleason I T1a-c T2a T1-2a N0 M0 < 10 X < 6 X IIA T1a-c T2a T2b N0 M0 <20 < 10, <20 <20 X 7 < 6 < 7 X IIB T2c T1-2 N0 M0 Any >20 Any >8 III T3a-bN0M0Any IV T4 Any T NO N1 Any M0 M1 Any

31. Clinical, Pathologic, Collaborative Staging Clinical (cT, cN, cM) –Before initiation of primary treatment –Important in deciding primary treatment Pathologic (pT, pN, pM) –From resected tissues Collaborative (CS) –Clinical, pathologic staging AND nonanatomic (site- specific) factors Implemented by the cancer registries Stage derived through computer algorithms

32. Collaborative staging: example 65 yo male with cT3, cN0 colon cancer Preoperative imaging does not demonstrate metastasis, cM0 Patient undergoes resection Pathology is pT3N1 –Pathology cannot really decide if M0, especially when no specimen was sent for evaluation of metastases Collaborative stage is: T3N1M0 – Stage IIIA The “STAGE” is a combination of pathologic and clinical findings

33. NCCN Guidelines Version 3.2012 Colon Cancer PATHOLOGIC STAGE SURVEILLANCE ADJUVANT THERAPY T1-3, N1-2, M0 Or T4, N1-2, MO History and PE every 3 – 6m for 2 y, then every 6 m for a total of 5y CEA every 3 – 6m for 2 y, then every 6 m for a total of 5y Chest/abdominal/pelvic CT annually x 3 -5y Colonoscopy in 1y except if no preoperative colonoscopy due to obstructing lesion, colonoscopy in 3-6m; if advanced adenoma, repeat in 1y; if no advanced polyp, repeat in 3y, then every 5 y PET-CT scan is not reoutinely recommended See Principles of Survivorship FOLFOX (category 1) preferred Other options include: FLOX (category 1) Or CapeOx (category 1) Or Capecitabine Or 5FU/Leucovorin COL-4

34. Changes in 2010 Revision cycle = 6 – 8 years –AJCC Cancer Staging Manual (Version 7), published Nov 2009 Applied to cancer cases from January 2010 –AJCC Cancer Staging Manual (Version 8), published in late 2015 Applied to cancer cases from January 2016 Lung –T subcategories (T(n) a,b) –Nodes by zones (not specific nodal stations) –Contralateral disease = M1a Colon –N subcategories (N1a – c; N2a - b) –M subcategories (M1a – single site, M1b – multiple sites) Breast –Stage I subcategories (IA, 1B – includes LN with micrometastases)

35. Limitations of Staging Not used in hematologic malignancies –Ann Arbor Staging System Not used in pediatric cancer Not useful in rare diseases –Not enough cases to stratify T, N, M Merkel Cell Cancer –Lumping different histopathologic subtypes Soft tissue sarcoma: multiple histologies Dominated by anatomic pathology and histology (size, nodes, histopathology, grade) –Gradually incorporating other prognostic variables

36. Future of staging Refined clinically –Number of lymph nodes in CRC –Ulceration in melanoma Molecular markers –Microarray research to determine prognosis based on patterns –Oncotype DX in breast cancer, in CRC Post treatment staging vs. pretreatment staging –Rectal cancer – does pretreatment staging matter if the patient has a complete pathological response to chemoradiation?

37. Staging in the future? Essential Factors TNM categories Histologic grade Extramural venous invasion Obstruction Quality of surgery Additional Factors Grade Tumor perforation Perineural invasion Invasion pattern Peritumoral lymphoid reaction Medullary type CEA serum level Number of lymph nodes Resected New and Promising Factors Microsatellite instability LOH 18q status P53 DNA ploidy VEGF, Kras expression 20q copy number Greene, CA Cancer J Clin 2008; 58:180- 90

38. Responsibilities Completion of forms –Accurate –Timely Completed staging within 4 months of initial treatment Clinical staging before patient receives initial treatment –Attendings must sign and are ultimately responsible – in particular for the clinical staging Use of patient stage in notes, presentations Use of Stage in multidisciplinary conferences –References to NCCN guidelines in treatment

39. Never wonder. By means of addition, subtraction, multiplication, and division, settle everything somehow. Charles Dickens, Hard Times, 1853

40. Acknowledgements Ina Ervin, Registrar (Emeritus) Kelli Olsen, Registrar COH Tumor Registry ACS, Commission on Cancer National Comprehensive Cancer Network

41. References Gunderson LL et.al. Revised Tumor and Node Categorization for Rectal Cancer Based on Surveillance, Epidemiology, and End Results and Rectal Pooled Analysis Outcomes, JCO Jan 10, 2010:256-263; published online on November 30, 2009 Kligerman, S. and G. Abbott (2010). "A Radiologic Review of the New TNM Classification for Lung Cancer." Am. J. Roentgenol. 194(3): 562- 573. AJCC Committee, AJCC Staging Manual, Version 7, Springer-Verlag, 2009. Greene FL. The Staging of Cancer: A Retrospective and Prospective Appraisal, CA Cancer J Clin 2008;58;180-190 http://www.nccn.org/professionals/physician_gls/f_guidelines.asp